Targeting vascular disrupting agent-treated tumor microenvironment with tissue-penetrating nanotherapy

Area of Science:

• Oncology
• Nanomedicine
• Molecular Biology

Background:

• Vascular disrupting agents (VDAs) induce tumor necrosis but often lead to regrowth.
• Tumor microenvironment (TME) modifications post-VDA treatment remain incompletely understood.
• Developing strategies to enhance the efficacy of VDA therapy is crucial for improved cancer treatment outcomes.

Purpose of the Study:

• To investigate if VDA treatment sensitizes tumors to secondary nanotherapy.
• To evaluate the efficacy of iRGD peptide-mediated nanoparticle delivery in VDA-treated tumors.
• To assess the combined therapeutic effect of VDAs, iRGD, and novel nanomedicine.

Main Methods:

• Mice with peritoneal carcinomatosis and breast cancer were treated with combretastatin A-4 phosphate (CA4P), a VDA.
• Upregulation of iRGD receptors (αv-integrins and NRP-1) was assessed post-VDA treatment.
• Nanoparticles loaded with Utorubicin (UTO-PS) were co-administered with iRGD in CA4P-treated mice.
• Tumor accumulation, distribution, and overall tumor burden were quantified.

Main Results:

• CA4P treatment upregulated αv-integrins and NRP-1 in peripheral tumor tissues.
• Co-administration of iRGD increased nanoparticle accumulation threefold and improved distribution in peritoneal carcinomatosis.
• Combination therapy (CA4P, iRGD, UTO-PS polymersomes) significantly reduced tumor burden in mice.
• The combination therapy demonstrated minimal overt toxicities.

Conclusions:

• VDA-induced molecular changes in the TME can be exploited for enhanced nanotherapy.
• iRGD peptide potentiates nanoparticle delivery to VDA-treated tumors.
• Sequential VDA and iRGD-enhanced nanotherapy offers a promising strategy for reducing tumor burden in certain cancers.